Safe and effective topical microbicides are urgently needed to curb the continued transmission of HIV-1 and other sexually transmitted infections. Microbicides with specific anti-HIV activity combined with excipients with their own anti-HIV properties may prove to be effective when used topically. The non-nucleoside reverse transcriptase inhibitor, UC781 may be ideally suited for this purpose. A major concern with vaginally applied, topical microbicides has been epithelial disruption and inflammation in the female genital tract which may create a paradoxical effect of enhancing HIV transmission. More sensitive methods to detect inflammatory changes and potentially harmful alterations in protective vaginal microflora associated with microbicide use are needed. In this project, we plan to combine our expertise in performing clinical trials with our ability to measure subtle changes in vaginal microflora and potentially sensitive indicators of inflammatory changes in the genital tract. In Project 5, we intend to study systemic and tissue absorption of UC781 and other microbicides developed in this program as well as safety, toxicity, and acceptability. We will further evaluate the effects of microbicides on vaginal microflora, cervical neutrophils and proinflammatory cytokines, and on the lower genital tract epithelium. Specifically, we plan to: (1) establish in humans the safety, toxicity, and acceptability of UC781 as a topical microbicide with and without other active agents. We will study systemic and local effects including gross and colposcopic evaluation of the lower female genital tract. We will evaluate changes in vaginal microflora and cervical neutrophils and inflammatory cytokines; (2) determine human pharmacokinetics of UC781; (3) assess the bioactivity, and concentration of UC781 and its metabolites in the vagina over time; and (4) determine tissue concentrations of microbicides and proinflammatory cytokines along the upper genital tract of women exposed to UC781.